The present invention relates to agmatine, a naturally occurring compound, and to novel derivatives thereof, and to hydrazine and polyamine derivatives, medicating compositions containing them, and the use thereof, especially in the treatment of acute neurotrauma (such as stroke) and degenerative disorders of the central and peripheral nervous system (such as dementia).
Agmatine. This naturally occurring compound is utilized mainly as a precursor for polyamine synthesis. Agmatine synthesis by decarboxylation of arginine, is catalyzed by the enzyme arginine decarboxylase (ADC) which is present in bacteria, plants and some invertebrates, but not in higher animals (Tabor C W & Tabor H. Ann Rev Biochem 53:749, 1984). Agmatine metabolism in animals is largely unknown.
Agmatine has been reported to possess a wide range of activities related to functions of the nervous system. Such activities include interaction with membrane receptors, such as nicotine, NMDA and intracellular imidazoline receptors. It can serve as ADP-ribose acceptor and thereby inhibit ADP-ribosylation of proteins. Agmatine may prevent collagen cross-linking in diabetes and aging, and may regulate epithelial cell growth in wound healing. Agmatine produces insulin-like effects in animals. Agmatine may serve as a precursor for biosynthesis of polyamines, compounds that possess a wide range of activities both within and external to the central nervous system (e.g., modulation of postsynaptic receptors, such as N-methyl-D-aspartate (NMDA), nicotinic and benzodiazepine receptors, antiplatelet, antiinflammatory and anticoagulant activities); The effect of the polyamines spermine, spermidine and putrescine in protecting against ischemia-induced nerve cell death in gerbils were described by Gilad G. M. et al. [Life Sci (1989) 44:1963-1969; Exp Neurol (1991) 111:349-355; Biochem Pharmacol (1992) 44:401-407]. Various molecules containing an aliphatic polyaminoguanidine chain have been synthesized and screened in a variety of animal models of central nervous system disorders. Many of these compounds have been based on toxins extracted from spiders (e.g. A. aperta and Argiopelabata) and the wasp triangulum. These compounds comprise a long poly(aminoalkane) chain (related to polyamines) linked to an aromatic or heterocyclic group through a carbonyl group. Disadvantages associated with using the polyamines and derivatives, relate to various toxic side effects that would hinder these compounds from proceeding to clinical use.
Importantly, agmatine not only proved to be relatively non-toxic, but at some concentrations it rather accelerates cell proliferation.
New findings on the activity of agmatine in laboratory models of neurotrauma, constituting part of the basis for this invention, will be described herein.
A disadvantage associated with using agmatine itself for chronic central nervous system disorders relates to transport through biological membranes.